It is well known, that in most cases, viral infections and tumor diseases attenuate the immune response of the organism, thereby activating the pathogenic micro-flora. That’s why the design and synthesis of novel antibiotics, particularly semi-synthetic penicillins and cephalosporins, having antitumor, antiviral and immunostimulating properties attracts a lot of interest.

The project deals with the synthesis and investigation of new antibiotic compounds, in search of drugs having high antitumor and antiviral activities. The development of rational approaches to the synthesis of a similar class of physiologically active compounds will be based on the comprehensive study and analysis of their structure–biological properties relationships.

The more important peculiarity of this project is the possibility to discover and investigate on novel compounds having antibacterial, antitumor and antiviral (including HIV) properties. This approach will hopefully allow to obtain information on the relationship between their chemical structural features and their biological properties.

Objectives of the Research Project

The main idea for constructing new structures lies in combination of structural fragments of known biologically active compounds. We are going to synthesize hybrid molecules containing structural elements from Penicillins, Cephalosporins (antibiotics), Sarkomycin (natural antitumor antibiotic), Amidinomycin (natural antiviral antibiotic), and Loviride (HIV-1 RT inhibitor). It is assumed that such hybrid molecules could show biological activity coming from various structural fragments.

Working for many years with such antibiotics as Sarkomycin and Amidinomycin, we studied the correlation of chemical structure and biological activity. We synthesized new derivatives of the above named groups of antibiotics showing high biological activity.

Some analogs of Sarkomicin have shown antitumor activity (on sarkoms C-180, C-37 and C-45, tumor growth inhibition ranged from 42 to 73%).

The analogs of Amidinomycin exhibit antiviral in vitro activity (when tested with influenza virus strain A/Aichi and variola vera) at a about the same level as Remantadin. It is worth mentioning that some analogs of amidinomycin show an interferon induction property too.

In last years we have also synthesized compounds belonging to the group of the 2-arylprolines, containing Loviride structural fragments. These compounds were able to inhibit the DNA polymerase activity of HIV-1 reverse transcriptase (both the wild-type and the drug-resistant mutant K103N/Y181C RTs). Their 50% inhibitory concentration (IC₅₀) ranged from 10^-3 to 10^-5 M.

The class of the 2-aryl or heterylprolines allowed us to design and synthesize compounds in which structural fragments from Penicillins, Cephalosporins, Sarkomycin, Amidinomycin and Loviride might be combined. That’s why we propose to develop new effective methods for synthesizing derivatives of 2-aryl or heterylprolines.

These compounds might be considered as analogs of nucleosides in which the sugar residue is substituted by the pyrrolidine ring.

Research Methods.

1.Synthesis of new compounds.

– The method of synthesis of new derivatives of N-aryl(or heteryl)-2-pyrrolidinecarboxylic acid has been developed in our Lab and described in [3].

2. The Physical-Chemical investigation of synthesized compounds and theoretical calculations.

– The single crystal X-ray investigations will be carried out on an automatic 4-circle diffractometer CAD-4 “Enraf-Nonius”.

3. Biological testing of synthesized compounds.

– In vivo and in vitro testing of antitumor, antiviral and antibacterial properties of synthesized compounds.

Expected Results.

The realization of this project may be important step to the understanding of mechanisms of an activity for the given class of compounds. It will be possible to plan and realize synthesis of biologically active compounds, in which antibacterial, antitumor, antiviral properties might be combined.

– It may introduce an essential contribution to the chemistry of antibiotics.

The Realization of the Project will allow to solve the row of the problems, answering ISTC purposes:

– Reorientation of the group of scientists and specialists, earlier occupied in sphere of the weapon science, on decision of pacific human problems.

The Project will be executed by group highly qualified scientists and specialists, earlier involved in military programs of former USSR. The IFOC and MSRC NAS RA possess the necessary conditions for successful realization of the project. In different stages of the program specialists from other interested organization will be involved in project as well as. The successful execution of the project is guaranteed experience of scientists involved in project and preliminary results of the studies, a part from which is published in listed below to literature. Authors of the Project invite to cooperation scientific groups, exploratory organizations and companies from countries of European Union, USA, Japan as well as from other countries, which may be interested by our project. We offer also undertaking joint seminar and scientific studies.

Publications/presentation.

1. Martirosyan, A., Gasparyan, S., Chachoyan, A., Hovhannesyan, V., Mnjoyan, Sh., Gharibjanyan, B.: New synthetic analogs of sarkomycin. IV. Acylation amino acids and peptides with 1-phenyl-2-methyl-3-oxo-1-cyclopentanecarboxylic acid. Chemotherapy of Tumors 60, 135-140, 1993.

2. Martirosyan, A., Hovhannesyan, V., Chachoyan, A., Gasparyan, M., Jaghacpanyan, N., Gasparyan, S., Mnjoyan, Sh., Gharibjanyan, B., Camalyan, L.: New synthetic analogs of amidinomycin. I. Searches of compounds with antitumor, antiviral and interferon induction activity on a basis of modification of amidinomycin`s structure. Chemotherapy of Tumors in the USSR 56, 75-80, 1991.

3. Martirosyan, A., Gasparyan, S., Hovhannesyan, V., Mnjoyan, Sh., Aleksanyan, M., Nikishchenko, M., Babayan, G.: New method of synthesis of the 2-phenylproline and its analogs. Chemistry of Heterocyclic Compounds 4, 488-492, 2000.

4. Tamazyan, R., Karapetyan, H., Martirosyan, A., Hovhannesyan, V., Gasparyan, S.: 1-Substituted derivatives of 2-phenylpyrrolidine-2-carboxamide. Acta Crystallografica C58, o386-o388, 2002.

5. Karapetyan, H., Tamazyan, R., Martirosyan, A., Hovhannesyan, V., Gasparyan, S.: 1-Substituted derivatives of 2-aryl-5-oxo-pyrrolidine-2-carboxylic acid. Acta Crystallografica C58, o399-o401, 2002.

6. Tamazyan, R., Karapetyan, H., Martirosyan, A., Martirosyan, V., Harutyunyan G., Gasparyan, S.: 1,2,5-Substituted derivatives of 2-phenylpyrrolidine. Acta Crystallografica C60, p.o390-o392, 2004.

7. Nersesyan L.E., Garibyan D.V., et al. The role of DNA methylation in tumor cells as a primary factor in regulation and treatment of malignant formations, Medical Science of Armenia, XLIII (2), p.37-40, 2003.

8. Yu.S.Babayan, A.E.Sngryan, D.V.Garibyan et. al., Interaction of antitumor drugs mtoxantrone and ametantrone with DNA as determined from changes in circular dichroism spectra. Biophysics, 43(3), p.398-402, 1998.